For treatment of malignant tumor, surgical therapy, chemotherapy, radiation therapy and the like are available. The treatment methods have certainly been improved in recent years due to the development of pharmaceutical agents used for chemotherapy, advanced surgical techniques and the like. For administration of antitumor agents, a single administration method (continuous, intermittent, large amount in short period), multidrug combination administration method, complex administration method with operation radiation therapy, topical administration method (tumor perfusion method, intraarterial administration method, intrabody cavity administration method), systemic administration method and the like are available. The administration of antitumor agents is based on location of primary cancer, sensitivity to pharmaceutical agents, presence or absence of metastasis, action mechanism of antitumor agents and the like and individual complex treatment methods for each cancer have been considered.
In general, however, the problem of side effects is inseparable in the treatment of malignant tumor with antitumor agents.
For example, bone marrow toxicity such as decrease in hematopoietic stem cells·bone marrow hypoplasia and the like, gastrointestinal tract toxicity and the like caused by alkylating agents, bone marrow toxicity, gastrointestinal tract toxicity, hepatopathy and the like caused by antimetabolite, cardiotoxicity, hemotoxicity, pulmonary toxicity (pulmonary fibrosis) and the like caused by anticancer antibiotic, neurotoxicity, bone marrow toxicity and the like caused by plant-derived anticancer agent, renal disorder, gastrointestinal tract toxicity and the like caused by platinum complex compound (particularly, nephrotoxicity is feared with regard to cisplatin, which is dealt with by intake of a large amount of water to reduce damage on kidney) are representative side effects.
When acute side effects occur, such as strong nausea, vomitus, diarrhea, allergy reaction, stomatitis, fever (40° C. or above), tachycardia·arrhythmia and hypotension, the dose of antitumor agents is reduced or the administration is interrupted. When chronical side effect and/or organ disorders such as myelopathia, severe infectious diseases, hepatopathy, hypofibrinogenemia, abnormal finding in lung, indication of cardiac failure, renal disorder and nervous symptom appear, administration of antitumor agents is completely stopped.
As mentioned above, these side effects are the factors limiting the dose of antitumor agents and pose serious issues, because side effects force reduction of dose and discontinuation of medication despite the effect provided by the agents.
While concurrent use of antitumor agents for the treatment of malignant tumor is one of the therapies employed, the combined use of the existing antitumor agents generally causes side effects such as potentiation of bone marrow suppression and the like. Therefore, strict attention to the dose, such as reduction of dose while continuously monitoring the condition of patients and the like becomes warranted. The combination of particular antitumor agents, too, is associated with the problem of side effects as in the case of single administration, because side effects that require particularly careful handling appear, such as cardiotoxicity by the combination of cyclophosphamide or ifosfamide and pentostatin, myelopathia by the combination of fluorouracil drug and sorivudine (antivirus agent), nervous disorder by the combination of vinca alkaloid pharmaceutical agent and platinum complex compound, and respiratory disorder by the combination of vinca alkaloid drug and mitomycin C.
With the aim of potentiation of antitumor effect and reduction of side effects, administration of different pharmaceutical agents having an effect on the antitumor agent before and after administration of antitumor agents and during administration thereof has been tried in recent years (e.g., fluorouracil and leucovorin, fluorouracil and thymidine, combination drug (UFT) of tegafur and uracil, administration of methotrexate prior to administration of fluorouracil and the like).
However, these attempts have not provided a sufficient treatment effect on malignant tumor.
In contrast, it has been clarified that Rho is activated upon receipt of signals from various cell membrane receptors, and the activated Rho functions via actomyosin system as a molecular switch of various cellular phenomena, such as smooth muscle constriction, cell motility, cell adhesion, morphological changes in the cell, cell growth and the like. Moreover, an important role played by Rho kinase, which is present in the downstream of the signal transduction pathway via Rho, in the above-mentioned responsive cell phenomena by Rho is being clarified.
In addition, a compound of the formula (I) to be mentioned later has been recently reported (WO98/06433) as a compound having a Rho kinase inhibitory activity. Certain isoquinolinesulfonamide derivative and isoquinoline derivative are also reported to show a Rho kinase inhibitory activity (WO98/06433 and Naunyn-Schmiedeberg's Archives of Pharmacology 385(1) Suppl., R219, 1998). Furthermore, it has been reported that ethacrynic acid, certain vinyl benzene derivatives such as 4-[2-(2,3,4,5,6-pentafluorophenyl)-acryloyl]cinnamic acid and the like and cinnamic acid derivative have a Rho kinase inhibitory activity (WO00/57914, JP-A-2000-44513).
The pharmaceutical use of a compound having a Rho kinase inhibitory activity is disclosed in WO98/06433, and described to be extensively useful as a therapeutic agent of hypertension, a therapeutic agent of angina pectoris, a cerebrovascular spasm suppressant, a therapeutic agent of asthma, a therapeutic agent of peripheral circulatory disturbance, a premature delivery preventive, a therapeutic agent of arterial sclerosis, an anticancer drug, an anti-inflammatory agent, an immunosuppressant, a therapeutic agent of autoimmune diseases, an anti-AIDS agent, a therapeutic agent of osteoporosis, a therapeutic agent of retinopathy, a cerebral function improver, a contraceptive drug, and a gastrointestinal tract infection preventive.
Furthermore, the compound of formula (I) has been already known to be useful as an agent for the prophylaxis or treatment of disorders of circulatory organs, such as coronary, cerebral, renal, peripheral artery and the like (e.g., a therapeutic agent of hypertension, a therapeutic agent of angina pectoris, a therapeutic agent of renal and peripheral circulation disorder, a suppressive agent of cerebrovascular contraction and the like), which is potent and long lasting, and also as a therapeutic agent of asthma (JP-A-62-89679, JP-A-3-218356, JP-A-4-273821, JP-A-5-194401, JP-A-6-41080 and WO95/28387).
The isoquinolinesulfonamide derivative described in the above-mentioned WO98/06433 is known to be effective as a vasodilating agent, a therapeutic agent of hypertension, a cerebral function improver, an anti-asthma agent, a heart protecting agent, a platelet aggregation inhibitor, a therapeutic agent of neurologic manifestation, an anti-inflammatory agent, an agent for the prevention and treatment of hyperviscosity syndrome, a therapeutic agent of glaucoma, a diminished tension agent, a motor paralysis improver of cerebral thrombosis, an agent for prevention and treatment of virus infection and transcriptional control factor inhibitor (JP-A-57-200366, JP-A-61-227581, JP-A-2-256617, JP-A-4-264030, JP-A-6-56668, JP-A-6-80569, JP-A-6-293643, JP-A-7-41424, JP-A-7-277979, WO97/23222, JP-A-9-227381, JP-A-10-45598 and JP-A-10-87491).
Moreover, the isoquinoline derivative described in the above-mentioned publication (Naunyn-Schmiedeberg's Archives of Pharmacology 385(1) Suppl., R219, 1998) is known to be useful as an agent for the prevention or treatment of brain tissue disorder due to vasospasm (WO97/28130).
From the foregoing, it has been clarified that Rho and Rho kinase are involved in the formation of tumor and induction of infiltration and metastasis of cancer cells, and that a compound having a Rho kinase inhibitory activity is useful as an antitumor agent.
However, there has been no report on potentiation of the antitumor effect of different antitumor agents by a compound having a Rho kinase inhibitory activity.